Developmental neurogenetic diseases can only be studied, and potentially treated, once systems to predictably deliver and express genes in neuronal cells are developed. We will utilize herpes simplex virus (HSV) as a vector for expressing genes in neuronal cells. This human DNA virus, for which about 90% of the U.S. population is seropositive, forms latent infections which persist for the lifetime of the individual. Using II$V derived vectors, we will study the nervous system component of a lysosomal storage disease. Lysosomal storage in neurons results in severe mental retardation in most children with these diseases. Specifically, we will use a beta-glucuronidase-negative-mouse (gus(mps)/gus(mps), with mucopolysaccharidosis (MPS) type VII (Sly disease), as an animal model. During the previous grant period we inserted a beta-glucuronidase gene into HSV- l, under control of the only viral promoter that is active during latency. We demonstrated that the recombinant vector could move from the periphery to the central nervous system. By using this promoter we achieved long term expression of the corrected gene in the nervous system of diseased mice. We now wish to continue our studies by examining the factors that increase GUSB activity in neuronal cells, and increase the number of corrected cells to bring vector correction to a level that will change the clinical disease. We will develop a simple system for inserting genes into HSV in order to increase our capacity to generate recombinant viruses for gene transfer studies. This will accelerate the development of effective vectors by increasing the number of design variations that can be tested. The goal of these studies is to address the problem of treatment of neurogenetic diseases by developing a method of expressing genes in the nervous system in vivo using a ubiquitous human virus. These studies will also provide a method for studying gene regulation in neuronal cells in vivo using the state of the art techniques of molecular biology.